title: GARP is regulated by miRNAs and controls latent TGF-β1 production by human regulatory T cells.
abstract: GARP is a transmembrane protein present on stimulated human regulatory T lymphocytes (Tregs), but not on other T lymphocytes (Th cells). It presents the latent form of TGF-β1 on the Treg surface. We report here that GARP favors the cleavage of the pro-TGF-β1 precursor and increases the amount of secreted latent TGF-β1. Stimulated Tregs, which naturally express GARP, and Th cells transfected with GARP secrete a previously unknown form of latent TGF-β1 that is disulfide-linked to GARP. These GARP/TGF-β1 complexes are possibly shed from the T cell surface. Secretion of GARP/TGF-β1 complexes was not observed with transfected 293 cells and may thus be restricted to the T cell lineage. We conclude that in stimulated human Tregs, GARP not only displays latent TGF-β1 at the cell surface, but also increases its secretion by forming soluble disulfide-linked complexes. Moreover, we identified six microRNAs (miRNAs) that are expressed at lower levels in Treg than in Th clones and that target a short region of the GARP 3' UTR. In transfected Th cells, the presence of this region decreased GARP levels, cleavage of pro-TGF-β1, and secretion of latent TGF-β1.
authors.affiliation: WELBIO and de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Gauthy
authors.forename: Julia
authors.initials: J
authors.lastname: Cuende
authors.forename: Julie
authors.initials: J
authors.lastname: Stockis
authors.forename: Caroline
authors.initials: C
authors.lastname: Huygens
authors.forename: Bernard
authors.initials: B
authors.lastname: Lethé
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Collet
authors.forename: Guido
authors.initials: G
authors.lastname: Bommer
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
authors.forename: Sophie
authors.initials: S
authors.lastname: Lucas
mesh_terms: D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C087215:LRRC32 protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; D008156:Luciferases